XBP1s acts as a transcription factor of IRE1? and promotes proliferation of colon cancer cells

Upon ER stress, IRE1 alpha is activated to splice XBP1 mRNA to generate XBP1s, a transcription factor that induces the expression of genes to cope with the stress. Expression of IRE1 alpha is elevated in cancers and the IRE1 alpha-XBP1s axis plays an important role in proliferation of cancer cells. However, the underlying mechanism is not well known. We found that ER stressors induced the expression of IRE1 alpha, which was inhibited by depletion of XBP1s. XBP1s bound IRE1 alpha promoter and initiated the transcription of IRE1 alpha. These data indicate that XBP1s acts as a transcription factor of IRE1 alpha. Overexpression of XBP1s increased the phosphorylation of JNK, a substrate of IRE1 alpha kinase, which was inhibited by IRE1 alpha kinase inhibitor Kira8. Overexpression of XBP1s also activated the regulated IRE1-dependent decay of mRNAs, which was suppressed by IRE1 alpha RNase inhibitor STF083010. Moreover, we found that expression of XBP1s promoted proliferation of colon cancer cells, which was abrogated by Kira8 and STF083010. The results suggest that XBP1s functions to induce IRE1 alpha expression and promote cancer cell proliferation. Our findings reveal a previously unknown mechanism of IRE1 alpha expression by XBP1s and highlight the role of this regulation in proliferation of colon cancer cells, suggesting that IRE1 alpha-targeting is a potential therapeutic strategy for colon cancer.